Traumatic Brain Injury Procedures Research Articles

Modulating chronic outcomes after pediatric traumatic brain injury: Distinct effects of social and environmental enrichment

Impairments in social and cognitive function are a common consequence of pediatric traumatic brain injury (TBI). Rehabilitation has the potential to promote optimal behavioral recovery. Here, we evaluated whether an enhanced social and/or cognitive environment could improve long-term outcomes in a preclinical model of pediatric TBI. Male C57Bl/6 J mice received a moderately-severe TBI or sham procedure at postnatal day 21. After one week, mice were randomized to different social conditions (minimal socialization, n = 2/cage; or social grouping, n = 6/cage), and housing conditions (standard cage, or environmental enrichment (EE), incorporating sensory, motor, and cognitive stimuli). After 8 weeks, neurobehavioral outcomes were assessed, followed by post-mortem neuropathology. We found that TBI mice exhibited hyperactivity, spatial memory deficits, reduced anxiety-like behavior, and reduced sensorimotor performance compared to age-matched sham controls. Pro-social and sociosexual behaviors were also reduced in TBI mice. EE increased sensorimotor performance, and the duration of sociosexual interactions. Conversely, social housing reduced hyperactivity and altered anxiety-like behavior in TBI mice, and reduced same-sex social investigation. TBI mice showed impaired spatial memory retention, except for TBI mice exposed to both EE and group housing. In the brain, while TBI led to significant regional tissue atrophy, social housing had modest neuroprotective effects on hippocampal volumes, neurogenesis, and oligodendrocyte progenitor numbers. In conclusion, manipulation of the post-injury environment has benefit for chronic behavioral outcomes, but the benefits are specific to the type of enrichment available. This study improves understanding of modifiable factors that may be harnessed to optimize long-term outcomes for survivors of early-life TBI.

Incidence of emergency neurosurgical TBI procedures: a population-based study

BackgroundThe rates of emergency neurosurgery in traumatic brain injury (TBI) patients vary between populations and trauma centers. In planning acute TBI treatment, knowledge about rates and incidence of emergency neurosurgery at the population level is of importance for organization and planning of specialized health care services. This study aimed to present incidence rates and patient characteristics for the most common TBI-related emergency neurosurgical procedures.MethodsOslo University Hospital is the only trauma center with neurosurgical services in Southeast Norway, which has a population of 3 million. We extracted prospectively collected registry data from the Oslo TBI Registry – Neurosurgery over a five-year period (2015–2019). Incidence was calculated in person-pears (crude) and age-adjusted for standard population. We conducted multivariate multivariable logistic regression models to assess variables associated with emergency neurosurgical procedures.ResultsA total of 2151 patients with pathological head CT scans were included. One or more emergency neurosurgical procedure was performed in 27% of patients. The crude incidence was 3.9/100,000 person-years. The age-adjusted incidences in the standard population for Europe and the world were 4.0/100,000 and 3.3/100,000, respectively. The most frequent emergency neurosurgical procedure was the insertion of an intracranial pressure monitor, followed by evacuation of the mass lesion. Male sex, road traffic accidents, severe injury (low Glasgow coma score) and CT characteristics such as midline shift and compressed/absent basal cisterns were significantly associated with an increased probability of emergency neurosurgery, while older age was associated with a decreased probability.ConclusionsThe incidence of emergency neurosurgery in the general population is low and reflects neurosurgery procedures performed in patients with severe injuries. Hence, emergency neurosurgery for TBIs should be centralized to major trauma centers.

Minocycline fails to treat chronic traumatic brain injury-induced impulsivity and attention deficits

Traumatic brain injury (TBI) impacts millions worldwide and can cause lasting psychiatric symptoms. Chronic neuroinflammation is a characteristic of post-injury pathology and is also associated with psychiatric conditions such as ADHD and bipolar disorder. Therefore, the current study sought to determine whether TBI-induced impulsivity and inattention could be treated using minocycline, an antibiotic with anti-inflammatory properties. Rats were trained on the five-choice serial reaction time task (5CSRT), a measure of motor impulsivity and attention. After behavior was stable on the 5CSRT, rats received either a bilateral frontal TBI or sham procedure. Minocycline was given at either an early (1 h post-injury) or chronic (9 weeks post-injury) timepoint. Minocycline was delivered every 12 h for 5 days (45 mg/kg, i.p.). Behavioral testing on the 5CSRT began again after one week of recovery and continued for 12 more weeks, then rats were transcardially perfused. Impulsivity and inattention were both substantially increased following TBI. Minocycline had no therapeutic effects at either the early or late time points. TBI rats had increased lesion volume, but minocycline did not attenuate lesion size. Additionally, microglia count measured by IBA-1+ cells was only increased acutely after TBI, and minocycline did not differentially change the number of microglia in TBI rats. Despite this, minocycline had clear effects on the gut microbiome. Based on the results of this study, minocycline may have limited efficacy for post-injury psychiatric-like symptoms.

Pharmacologic Inhibition of ADAM10 Attenuates Brain Tissue Loss, Axonal Injury and Pro-inflammatory Gene Expression Following Traumatic Brain Injury in Mice.

The α-secretase A disintegrin and metalloprotease 10 (ADAM10) regulates various physiological and pathophysiological processes. Despite its broad functional implications during development, plasticity, and disease, no pharmacological approaches to inhibit ADAM10 in acute brain injury have been reported. Here, we examined the effects of the ADAM10 inhibitor GI254023X on the neurological and histopathological outcome after experimental traumatic brain injury (TBI). C57BL/6N mice were subjected to the controlled cortical impact (CCI) model of TBI or sham procedure and received GI254023X or vehicle during the acute phase of injury (n = 40, 100 mg/kg, 25% DMSO, 0.1 M Na2CO3, intraperitoneal, 30 min and 24 h after TBI). GI254023X treatment did not improve neurological deficits from 1 to 7 days post-injury (dpi) but animals treated with GI254023X exhibited smaller brain lesions compared to vehicle treatment. Determination of brain mRNA expression by quantitative PCR showed that TBI-induced up-regulation of Adam10 and Adam17 was not influenced by GI254023X but the up-regulation of the matrix metalloproteinase genes Mmp2 and Mmp9 was attenuated. GI254023X treatment further increased the T cell marker Cd247 but did not affect blood brain barrier integrity, as assessed by Occludin mRNA expression and IgG brain extravasation. However, in agreement with neuroprotective effects of ADAM10 inhibition, GI254023X treatment attenuated axonal injury, as indicated by decreased generation of spectrin breakdown products (SBDPs) and decreased immunostaining using anti-non-phosphorylated neurofilament (SMI-32). Interestingly, reduced axonal injury in GI254023X-treated animals coincided with subtle mRNA dysregulation in the glutamate receptor subunit genes Gria1 and Grin2b. Quantitative PCR also revealed that GI254023X mitigated up-regulation of the pro-inflammatory markers Il6, Tnfa, and Lcn2 but not the up-regulation of the pan-microglia marker Aif1, the M2 microglia marker Arg1 and the reactive astrocyte marker Gfap. Taken together, the ADAM10 inhibitor GI254023X attenuates brain tissue loss, axonal injury and pro-inflammatory gene expression in the CCI model of TBI. These results suggest that ADAM10 may represent a therapeutic target in the acute phase of TBI.

Neuropathology and immune biomarker discovery in a rat model of Alzheimer's disease, TgF344‐AD, with controlled cortical injury model of traumatic brain injury

AbstractBackgroundIndividuals with a history of traumatic brain injury (TBI) have a higher risk of developing Alzheimer’s disease (AD) and AD‐related dementias (ADRD), such as chronic traumatic encephalopathy (CTE). However, the relationship(s) between TBI, AD, and CTE remain poorly understood and markedly understudied. Because transgenic mouse models of AD that develop amyloidosis do not readily develop pathological tauopathy that is commonly found in ADRD, we used the TgF344‐AD transgenic rat model of AD in which amyloid deposition drives endogenous tauopathy and neurodegeneration for our TBI studies.MethodWe used the closed‐head controlled cortical impact (CCI) model of TBI, performed either once (1X‐CCI) or twice over two weeks (2X‐CCI) in both 6‐ and 12‐month‐old TgF344‐AD and wild‐type (F344) rats to investigate the effects of TBI on acute and chronic neuroinflammation, on blood brain barrier (BBB) integrity, and on ADRD‐associated neuropathology. Whole brains and terminal blood draws were collected at different time points following the 1X‐ or 2X‐CCI TBI procedures at 3, 15, 30, 60, and 120 days after the final CCI procedure. Thus, the tissue collection ages of animals across the project allow for TBI‐induced ADRD‐related pathological analyses at 6, 7, 8, 10, 12, 13, 14, and 16 months of age. MRI scans were conducted at 30‐days post‐CCI to examine BBB leakage and chronic inflammation, with subsequent post‐mortem histochemical confirmation. Terminal blood draw samples were used for complete blood cell counts with differential and multiple biomarker analyses.ResultThis project is ongoing, but interim analyses reveal chronic neutrophil percentages remaining consistent in both TgF344‐AD and wild‐type 12‐month‐old cohorts undergoing either 1X‐ or 2X‐CCI at all post‐injury time points. Also, the upright time for the animals does not appear to differ based on impact type or genotype so far. However, histochemical pathological analyses of the 12‐month‐old AD rats have demonstrated changes in Aβ pathology and astrogliosis markers. MRI analyses have not yet been completed.ConclusionWe are continuing to carry out detailed analyses of changes in ADRD‐related pathology and blood biomarkers. These animal models should help provide an increased understanding of chronic neuroinflammation and other pathological mechanisms associated with TBI and risk for ADRD.

Combined Effects of Repetitive Mild Traumatic Brain Injury and Alcohol Drinking on the Neuroinflammatory Cytokine Response and Cognitive Behavioral Outcomes.

The relationship between alcohol consumption and traumatic brain injury (TBI) often focuses on alcohol consumption increasing the likelihood of incurring a TBI, rather than alcohol use outcomes after TBI. However, patients without a history of an alcohol use disorder can also show increased problem drinking after single or multiple TBIs. Alcohol and mild TBI share diffuse deleterious neurological impacts and cognitive impairments; therefore, the purpose of these studies was to determine if an interaction on brain and behavior outcomes occurs when alcohol is consumed longitudinally after TBI. To examine the impact of mild repetitive TBI (rmTBI) on voluntary alcohol consumption, mice were subjected to four mild TBI or sham procedures over a 2 week period, then offered alcohol (20% v/v) for 2 weeks using the two-bottle choice, drinking in the dark protocol. Following the drinking period, mice were evaluated for neuroinflammatory cytokine response or tested for cognitive and behavioral deficits. Results indicate no difference in alcohol consumption or preference following rmTBI as compared to sham; however, increases in the neuroinflammatory cytokine response due to alcohol consumption and some mild cognitive behavioral deficits after rmTBI and alcohol consumption were observed. These data suggest that the cytokine response to alcohol drinking and rmTBI + alcohol drinking is not necessarily aggregate, but the combination does result in an exacerbation of cognitive behavioral outcomes.

Administration of all-trans retinoic acid after experimental traumatic brain injury is brain protective.

All-trans retinoic acid (ATRA) is a vitamin A metabolite, important in the developing and mature brain. Pre-injury ATRA administration ameliorates ischaemic brain insults in rodents. This study examined the effects of post-traumatic ATRA treatment in experimental traumatic brain injury (TBI). Male adult mice were subjected to the controlled cortical impact model of TBI or sham procedure and killed at 7 or 30 days post-injury (dpi). ATRA (10 mg kg-1, i.p.) was given immediately after the injury and 1, 2 and 3 dpi. Neurological function and sensorimotor coordination were evaluated. Brains were processed for (immuno-) histological, mRNA and protein analyses (qPCR and western blot). ATRA treatment reduced brain lesion size, reactive astrogliosis and axonal injury at 7 dpi, and hippocampal granule cell layer (GCL) integrity was protected at 7 and 30 dpi, independent of cell proliferation in neurogenic niches and blood-brain barrier damage. Neurological and motor deficits over time and the brain tissue loss at 30 dpi were not affected by ATRA treatment. ATRA decreased gene expression of markers for damage-associated molecular pattern (HMGB1), apoptosis (caspase-3 and Bax), activated microglia (TSPO), and reactive astrogliosis (GFAP, SerpinA3N) at 7 dpi and a subset of markers at 30 dpi (TSPO, GFAP). In experimental TBI, post-traumatic ATRA administration exerted brain protective effects, including long-term protection of GCL integrity, but did not affect neurological and motor deficits. Further investigations are required to optimize treatment regimens to enhance ATRA's brain protective effects and improve outcomes.

Human Umbilical Cord–Derived Mesenchymal Stem Cell Therapy Effectively Protected the Brain Architecture and Neurological Function in Rat After Acute Traumatic Brain Injury

Intracranial hemorrhage from stroke and head trauma elicits a cascade of inflammatory and immune reactions detrimental to neurological integrity and function at cellular and molecular levels. This study tested the hypothesis that human umbilical cord–derived mesenchymal stem cell (HUCDMSC) therapy effectively protected the brain integrity and neurological function in rat after acute traumatic brain injury (TBI). Adult male Sprague-Dawley rats (n = 30) were equally divided into group 1 (sham-operated control), group 2 (TBI), and group 3 [TBI + HUCDMSC (1.2 × 106 cells/intravenous injection at 3 h after TBI)] and euthanized by day 28 after TBI procedure. The results of corner test and inclined plane test showed the neurological function was significantly progressively improved from days 3, 7, 14, and 28 in groups 1 and 3 than in group 2, and group 1 than in group 3 (all P < 0.001). By day 28, brain magnetic resonance imaging brain ischemic volume was significantly increased in group 2 than in group 3 (P < 0.001). The protein expressions of apoptosis [mitochondrial-bax positive cells (Bax)/cleaved-caspase3/cleaved-poly(adenosine diphosphate (ADP)-ribose) polymerase], fibrosis (Smad3 positive cells (Smad3)/transforming growth factor-β), oxidative stress (NADPH Oxidase 1 (NOX-1)/NADPH Oxidase 2 (NOX-2)/oxidized-protein/cytochrome b-245 alpha chain (p22phox)), and brain-edema/deoxyribonucleic acid (DNA)–damaged biomarkers (Aquaporin-4/gamma H2A histone family member X ( (γ-H2AX)) displayed an identical pattern to neurological function among the three groups (all P < 0.0001), whereas the protein expressions of angiogenesis biomarkers (vascular endothelial growth factor/stromal cell–derived factor-1α/C-X-C chemokine receptor type 4 (CXCR4)) significantly increased from groups 1 to 3 (all P < 0.0001). The cellular expressions of inflammatory biomarkers (cluster of differentiation 14 (+) cells (CD14+)/glial fibrillary acidic protein positive cells (GFAP+)/ a member of a new family of EGF-TM7 molecules positive cells (F4/80+)) and DNA-damaged parameter (γ-H2AX) exhibited an identical pattern, whereas cellular expressions of neural integrity (hexaribonucleotide Binding Protein-3 positive cells (NeuN+)/nestin+/doublecortin+) exhibited an opposite pattern of neurological function among the three groups (all P < 0.0001). Xenogeneic HUCDMSC therapy was safe and it significantly preserved neurological function and brain architecture in rat after TBI.

Socioeconomic Status Affects Outcomes After Severity-Stratified Traumatic Brain Injury

BackgroundSocioeconomic status (SES) and race have been shown to increase the incidence of being afflicted by a traumatic brain injury (TBI) resulting in worse posthospitalization outcomes. The goal of this study was to determine the effect disparities have on in-hospital mortality, discharge to inpatient rehabilitation, hospital length of stay (LOS), and TBI procedures performed stratified by severity of TBI. MethodsThis was a retrospective cohort study of patients with closed head injuries using the National Trauma Data Bank (2012-2015). Multivariate logistic/linear regression models were created to determine the impact of race and insurance status in groups graded by head Abbreviated Injury Scale (AIS). ResultsWe analyzed 131,461 TBI patients from NTDB. Uninsured patients experienced greater mortality at an AIS of 5 (odds ratio [OR] = 1.052, P = 0.001). Uninsured patients had a decreased likelihood of being discharged to inpatient rehabilitation with an increasing AIS beginning from an AIS of 2 (OR = 0.987, P = 0.008) to an AIS of 5 (OR = 0.879, P < 0.001). Black patients had an increased LOS as their AIS increased from an AIS of 2 (0.153 d, P < 0.001) to 5 (0.984 d, P < 0.001) with the largest discrepancy in LOS occurring at an AIS of 5. ConclusionsDisparities in race and SES are associated with differences in mortality, LOS, and discharge to inpatient rehabilitation. Patients with more severe TBI have the greatest divergence in treatment and outcome when stratified by race and ethnicity as well as SES.

Hypocretin Mediates Sleep and Wake Disturbances in a Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of disability worldwide. Post-TBI sleep and wake disturbances are extremely common and difficult for patients to manage. Sleep and wake disturbances contribute to poor functional and emotional outcomes from TBI, yet effective therapies remain elusive. A more comprehensive understanding of mechanisms underlying post-TBI sleep and wake disturbance will facilitate development of effective pharmacotherapies. Previous research in human patients and animal models indicates that altered hypocretinergic function may be a major contributor to sleep-wake disturbance after TBI. In this study, we further elucidate the role of hypocretin by determining the impact of TBI on sleep-wake behavior of hypocretin knockout (HCRT KO) mice. Adult male C57BL/6J and HCRT KO mice were implanted with electroencephalography recording electrodes, and pre-injury baseline recordings were obtained. Mice were then subjected to either moderate TBI or sham surgery. Additional recordings were obtained and sleep-wake behavior determined at 3, 7, 15, and 30 days after TBI or sham procedures. At baseline, HCRT KO mice had a significantly different sleep-wake phenotype than control C57BL/6J mice. Post-TBI sleep-wake behavior was altered in a genotype-dependent manner: sleep of HCRT KO mice was not altered by TBI, whereas C57BL/6J mice had more non-rapid eye movement sleep, less wakefulness, and more short wake bouts and fewer long wake bouts. Numbers of hypocretin-positive cells were reduced in C57BL/6J mice by TBI. Collectively, these data indicate that the hypocretinergic system is involved in the alterations in sleep-wake behavior that develop after TBI in this model, and suggest potential therapeutic interventions.

Increased Sleep Need and Reduction of Tuberomammillary Histamine Neurons after Rodent Traumatic Brain Injury.

Although sleep-wake disturbances are prevalent and well described after traumatic brain injury, their pathophysiology remains unclear, most likely because human traumatic brain injury is a highly heterogeneous entity that makes the systematic study of sleep-wake disturbances in relation to trauma-induced histological changes a challenging task. Despite increasing interest, specific and effective treatment strategies for post-traumatic sleep-wake disturbances are still missing. With the present work, therefore, we aimed at studying acute and chronic sleep-wake disturbances by electrophysiological means, and at assessing their histological correlates after closed diffuse traumatic brain injury in rats with the ultimate goal of generating a model of post-traumatic sleep-wake disturbances and associated histopathological findings that accurately represents the human condition. We assessed sleep-wake behavior by means of standard electrophysiological recordings before and 1, 7, and 28 days after sham or traumatic brain injury procedures. Sleep-wake findings were then correlated to immunohistochemically labeled and stereologically quantified neuronal arousal systems. Compared with control animals, we found that closed diffuse traumatic brain injury caused increased sleep need one month after trauma, and sleep was more consolidated. As histological correlate, we found a reduced number of histamine immunoreactive cells in the tuberomammillary nucleus, potentially related to increased neuroinflammation. Monoaminergic and hypocretinergic neurotransmitter systems in the hypothalamus and rostral brainstem were not affected, however. These results suggest that our rat traumatic brain injury model reflects human post-traumatic sleep-wake disturbances and associated histopathological findings very accurately, thus providing a study platform for novel treatment strategies for affected patients.

Clinical predictors of intracranial injuries on CT in infants younger than 2 years old with mild traumatic brain injury.

PurposeMild traumatic brain injury (TBI) is common in children. The aim of this study was to identify clinical predictors of intracranial injuries on computed tomography (CT) in infants younger than 2 years old with mild TBI, which allow reducing number of imaging.ResultsOf 214 enrolled infants with complete data, 30 (5.8%) sustained intracranial injuries. Younger age in months, severe injury mechanism and scalp hematomas were associated with traumatic intracranial injuries on CT. 71 had scalp hematomas and 143 had no scalp hematoma. Within infants with scalp hematomas, 26 sustained intracranial injuries and 45 presented normal. Intracranial injuries were significantly correlated with larger scalp hematomas and different scalp hematoma locations. Logistic regression analysis showed that scalp hematoma and mechanism of injury in infants younger than 2 years old with mild TBI was related to intracranial injuries (hazard ratio=38.291, P=0.0001; hazard ratio=0.174, P=0.001). In subgroup of mild TBI infants with scalp hematomas, logistic regression analysis showed age, scalp hematoma size and mechanism of injury were independently associated with intracranial injuries (hazard ratio=0.299, P=0.032; hazard ratio=5.272, P=0.006; hazard ratio=0.312, P=0.030).MethodsBetween 2014 and 2016, we retrospectively enrolled infants <2 years old with mild TBI. Data recorded included age, sex, mechanism of head injury, size and location of scalp hematoma, fracture and intracranial injuries on CT.ConclusionThe characteristics of scalp hematomas and mechanism of injury were associated with intracranial injuries. These factors should be considered when making decisions on radiologic examinations of infants < 2 years old with mild TBI and alternative procedures, which do not involve ionizing radiation, should be used if appropriate.

Calcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats

Traumatic brain injury (TBI) initiates a complex cascade of neurochemical and signaling changes that leads to neuronal apoptosis, which contributes to poor outcomes for patients with TBI. Previous study indicates that calcium-sensing receptor (CaSR) activation contributes to neuron death in focal cerebral ischemia-reperfusion mice, however, its role in neuronal apoptosis after TBI is not well-established. Using a controlled cortical impact model in rats, the present study was designed to determine the effect of CaSR inhibitor NPS2390 upon neuronal apoptosis after TBI. Rats were randomly distributed into three groups undergoing the sham surgery or TBI procedure, and NPS2390 (1.5 mg/kg) was infused subcutaneously at 30 min and 120 min after TBI. All rats were sacrificed at 24 h after TBI. Our data indicated that NPS2390 significantly reduced the brain edema and improved the neurological function after TBI. In addition, NPS2390 decreased caspase-3 levels and the number of apoptotic neurons. Furthermore, NPS2390 up-regulated anti-apoptotic protein Bcl-2 expression and down-regulated pro-apoptotic protein Bax, and reduced subsequent release of cytochrome c into the cytosol. In summary, this study indicated that inhibition of CaSR by NPS2390 attenuates neuronal apoptosis after TBI, in part, through modulating intrinsic apoptotic pathway.

Insurance status and race affect treatment and outcome of traumatic brain injury

BackgroundThere is increasing evidence that race and socioeconomic factors affect patient outcomes after traumatic brain injury (TBI). Our goal was to assess the effect of race, ethnicity and insurance status on hospital length of stay, procedures performed, mortality, and discharge disposition after TBI. MethodsThis was a retrospective cohort study using the National Trauma Data Bank (2002-2012) to analyze patients aged 14-89 y with one of five closed head injuries. Univariate regressions identified demographic and injury characteristics that were significant predictors of outcomes. These variables were then included in multivariate regression models. ResultsWe analyzed 187,354 TBI patients. The sample was 78% white, 9% black, 9% Hispanic, 3% Asian, and 1% native American, and included 42% Medicare, 30% private insurance, 12% uninsured, 8% other insurance, and 8% Medicaid. Compared with white patients, black and Hispanic patients were more likely to have a TBI procedure (blacks odds ratio [OR] = 1.19, P < 0.001; Hispanics OR = 1.33, P < 0.001), had longer hospital stays (blacks coeff = 1.02, P < 0.001; Hispanics coeff = 0.61, P < 0.001), were less likely to die in the hospital (blacks OR = 0.90, P = 0.006; Hispanics OR = 0.90, P = 0.007), and more (black OR = 1.09, P = 0.001) or less likely (Hispanic OR = 0.76, P < 0.001) to be discharged to rehabilitation. Compared with the privately insured, the uninsured were less likely to have a TBI procedure (OR = 0.90, P = 0.001), had longer hospital stays (coeff = 0.24, P < 0.001), were more likely to die in the hospital (OR = 1.37, P < 0.001), and less likely to be discharged to rehabilitation (OR = 0.53, P < 0.001). ConclusionsRace/ethnicity and insurance status significantly affect TBI patient outcomes, even after controlling for demographic and injury characteristics.

Chronic Exposure to Androgenic-Anabolic Steroids Exacerbates Axonal Injury and Microgliosis in the CHIMERA Mouse Model of Repetitive Concussion.

Concussion is a serious health concern. Concussion in athletes is of particular interest with respect to the relationship of concussion exposure to risk of chronic traumatic encephalopathy (CTE), a neurodegenerative condition associated with altered cognitive and psychiatric functions and profound tauopathy. However, much remains to be learned about factors other than cumulative exposure that could influence concussion pathogenesis. Approximately 20% of CTE cases report a history of substance use including androgenic-anabolic steroids (AAS). How acute, chronic, or historical AAS use may affect the vulnerability of the brain to concussion is unknown. We therefore tested whether antecedent AAS exposure in young, male C57Bl/6 mice affects acute behavioral and neuropathological responses to mild traumatic brain injury (TBI) induced with the CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) platform. Male C57Bl/6 mice received either vehicle or a cocktail of three AAS (testosterone, nandrolone and 17α-methyltestosterone) from 8–16 weeks of age. At the end of the 7th week of treatment, mice underwent two closed-head TBI or sham procedures spaced 24 h apart using CHIMERA. Post-repetitive TBI (rTBI) behavior was assessed for 7 d followed by tissue collection. AAS treatment induced the expected physiological changes including increased body weight, testicular atrophy, aggression and downregulation of brain 5-HT1B receptor expression. rTBI induced behavioral deficits, widespread axonal injury and white matter microgliosis. While AAS treatment did not worsen post-rTBI behavioral changes, AAS-treated mice exhibited significantly exacerbated axonal injury and microgliosis, indicating that AAS exposure can alter neuronal and innate immune responses to concussive TBI.

Puerarin ameliorates oxidative stress in a rodent model of traumatic brain injury

BackgroundA wealth of evidence has suggested that oxidative stress is involved in the secondary brain injury after traumatic brain injury (TBI). Recently, numerous in vivo and in vitro studies were reported that puerarin could inhibit oxidative stress through the activation of phosphatidylinositol 3-kinase (PI3K)-Akt pathway. It is unknown, however, whether puerarin can provide neuroprotection and reduce oxidative stress after TBI. The present study investigated the effects of puerarin on the TBI-induced neurodegeneration, oxidative stress, and the possible role of PI3K-Akt pathway in the neuroprotection of puerarin, in a rat model of TBI. Materials and methodsRats were randomly distributed into various subgroups undergoing the sham surgery or TBI procedures. Puerarin (200 mg/kg) was given intraperitoneally at 10 min before injury and PI3K-Akt pathway inhibitor LY294002 was also administered intracerebroventricular in one subgroup. All rats were killed at 24 h after TBI for examination. ResultsOur data indicated that puerarin could significantly reduce TBI-induced neuronal degeneration, accompanied by the partial restoration of the redox disturbance and enhanced expression of phospho-Akt in the pericontusional cortex after TBI. Moreover, PI3K-Akt pathway inhibitor LY294002 could partially abrogate the neuroprotection of puerarin in rats with TBI. ConclusionsThese results indicate that puerarin can ameliorate oxidative neurodegeneration after TBI, at least in part, through the activation of PI3K-Akt pathway.

Activation of metabotropic glutamate receptor 5 reduces the secondary brain injury after traumatic brain injury in rats

A wealth of evidence has shown that microglia-associated neuro-inflammation is involved in the secondary brain injury contributed to the poor outcome after traumatic brain injury (TBI). In vitro studies were reported that activation of metabotropic glutamate receptor 5 (mGluR5) could inhibit the microglia-associated inflammation in response to lipopolysaccharide and our previous study indicated that mGluR5 was expressed in activated microglia following TBI. However, there is little known about whether mGluR5 activation can provide neuro-protection and reduce microglia-associated neuro-inflammation in rats after TBI. The goal of the present study was to investigate the effects of mGluR5 activation with selective agonist CHPG, on cerebral edema, neuronal degeneration, microglia activation and the releasing of pro-inflammatory cytokines, in a rat model of TBI. Rats were randomly distributed into various subgroups undergoing the sham surgery or TBI procedures, and 250nmol of CHPG or equal volume vehicle was given through intracerebroventricular injection at 30min post-TBI. All rats were sacrificed at 24h after TBI for the further measurements. Our data indicated that post-TBI treatment with CHPG could significantly reduce the secondary brain injury characterized by the cerebral edema and neuronal degeneration, lead to the inhibition of microglia activation and decrease the expression of pro-inflammatory cytokines in both mRNA transcription and protein synthesis. These results provide the substantial evidence that activation of mGluR5 reduces the secondary brain injury after TBI, in part, through modulating microglia-associated neuro-inflammation.

Delayed hemorrhagic hypotension exacerbates the hemodynamic and histopathologic consequences of traumatic brain injury in rats.

Alterations in cerebral autoregulation and cerebrovascular reactivity after traumatic brain injury (TBI) may increase the susceptibility of the brain to secondary insults, including arterial hypotension. The purpose of this study was to evaluate the consequences of mild hemorrhagic hypotension on hemodynamic and histopathologic outcome after TBI. Intubated, anesthetized male rats were subjected to moderate (1.94 to 2.18 atm) parasagittal fluid-percussion (FP) brain injury. After TBI, animals were exposed to either normotension (group 1: TBI alone, n = 6) or hypotension (group 2: TBI + hypotension, n = 6). Moderate hypotension (60 mm Hg/30 min) was induced 5 minutes after TBI or sham procedures by hemorrhage. Sham-operated controls (group 3, n = 7) underwent an induced hypotensive period, whereas normotensive controls (group 4, n = 4) did not. For measuring regional cerebral blood flow (rCBF), radiolabeled microspheres were injected before, 20 minutes after, and 60 minutes after TBI (n = 23). For quantitative histopathologic evaluation, separate groups of animals were perfusion-fixed 3 days after TBI (n = 22). At 20 minutes after TBI, rCBF was bilaterally reduced by 57% +/- 6% and 48% +/- 11% in cortical and subcortical brain regions, respectively, under normotensive conditions. Compared with normotensive TBI rats, hemodynamic depression was significantly greater with induced hypotension in the histopathologically vulnerable (P1) posterior parietal cortex (P < 0.01). Secondary hypotension also increased contusion area at specific bregma levels compared with normotensive TBI rats (P < 0.05), as well as overall contusion volume (0.96 +/- 0.46 mm(3) vs. 2.02 +/- 0.51 mm(3), mean +/- SD, P < 0.05). These findings demonstrate that mild hemorrhagic hypotension after FP injury worsens local histopathologic outcome, possibly through vascular mechanisms.

Sequential changes in glial fibrillary acidic protein and gene expression following parasagittal fluid-percussion brain injury in rats.

This study documents the regional and temporal patterns of glial fibrillary acidic protein (GFAP) RNA and protein expression after parasagittal fluid-percussion (F-P) brain injury (1.7 to 2.2 atm) in male Sprague-Dawley rats. In situ hybridization was conducted in 28 rats with a 35S-labeled antisense riboprobe to GFAP at 0.5, 2, and 6 hours and 1, 3, and 30 days after traumatic brain injury (TBI) or sham procedures. Immunocytochemical staining of GFAP was conducted in 20 rats at 1, 3, 7, and 30 days after TBI or sham procedures. At 0.5 and 2 hours after TBI, increased GFAP mRNA was restricted to superficial cortical areas underlying the impact site. At 24 hours, increased GFAP mRNA was observed throughout the traumatized hemisphere except within the histopathologically vulnerable lateral parietal cortex and external capsule. Contralateral expression within the hippocampus and cingulate and lateral cortices was also observed. Three days after TBI, GFAP mRNA expression was prominent overlying pial surfaces, in cortical regions surrounding the contusion, and within the hippocampus and lateral thalamus. Immunocytochemical visualization of GFAP at 1 and 3 days demonstrated reactive astrocytes overlying the pial surface, surrounding the cortical contusion, and within ipsilateral white matter tracts, hippocampus, and lateral thalamus. At 30 days, GFAP mRNA and protein expression were present within the deeper cortical layers of the lateral somatosensory cortex and lateral thalamus and throughout ipsilateral white matter tracts. These data demonstrate a complex pattern of GFAP mRNA and protein expression within gray and white matter tracts following F-P brain injury. Patterns of GFAP gene expression may be a sensitive molecular marker for evaluating the global response of the brain to focal injury in terms of progressive neurodegenerative as well as regenerative processes.

Hippocampally dependent and independent chronic spatial navigational deficits following parasagittal fluid percussion brain injury in the rat

Previous reports have documented spatial navigational deficits following experimental traumatic brain injury (TBI), although the majority of the work to date has involved assessment at acute intervals following TBI, and has focused on tasks sensitive to hippocampal dysfunction. The present experiments were designed to investigate the chronic consequences of TBI, and the possible contribution of extrahippocampal dysfunction to TBI-induced spatial navigational deficits, in a moderate parasagittal fluid percussion TBI model. In Experiment 1, animals were pre-trained in a water maze, subjected to TBI or sham procedures, and re-evaluated in the water maze 48 h following the insult. Six to 8 weeks following TBI, the same animals were required to navigate to a different platform location. TBI animals exhibited significant deficits in retention of previously learned spatial information at the 48 h interval, and marginally impaired acquisition of a novel platform location during the chronic test sessions. In Experiment 2, animals were required to navigate to novel spatial locations using cued (to evaluate extrahippocampal function) as well as non-cued variants of the water maze task during the 8 week period following the insult. Injured animals exhibited deficits in both tasks which gradually diminished over the course of testing. The results of these experiments indicate that moderate TBI is accompanied by both retention and acquisition deficits, and that some of the navigational deficits observed in the water maze can be attributed to extrahippocampal damage. The possible recovery of spatial navigational ability following parasagittal TBI at moderate intensities is also discussed.